We propose that responses to noxious stimulation of cutaneous receptive fields are due to a complex interaction of serotonergic, adrenergic, cholinergic, and enkephalinergic neuronal systems in the midbrain, brain stem and spinal cord. Furthermore, we have outlined possible sites of action at which opiate analgesics may modify the interactions among these neuronal systems. These interactions will be examined by: (1) testing the effect of lesions placed in serotonergic, cholinergic and adrenergic nuclei on responses to noxious stimulation and opiate analgesias; (2) testing the effects of stimulating these nuclei on pain perception and opiate analgesia; (3) assessing the influence noradrenergic projections to the raphe magnus by electrical stimulation of norepinephrine-containing nuclei and ascertaining the effects on raphe magnus neurons; (4) microinjecting cholinergic and adrenergic agents into the raphe magnus to ascertain the influence of modifying cholinergic and adrenergic neurotransmission on the function of raphe magnus neurons; (5) testing the reactivity of identified serotonergic and non-serotonergic raphe magnus neurons to noxious stimuli and the iontophoretic application of putative neurotransmitters such as serotonin, norepinephrine, acetylcholine, and enkephalins.